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1 Neuroscience Research, Abbott Laboratories, Abbott Park, IL, USA
* To whom correspondence should be addressed. E-mail: Steve.P.McGaraughty{at}abbott.co.
Systemic administration of A-425619, a potent and selective TRPV1 receptor antagonist that dose not readily enter the CNS, produces antinociception in several rat models of pathological nociception, including complete Freund's adjuvant(CFA)-induced thermal hyperalgesia. In order to further understand the peripheral mechanisms of TRPV1-related antinociception, we examined the effects of systemic and site-specific injections of A-425169 on evoked and spontaneous firing of spinal wide dynamic range (WDR) neurons in uninjured rats and rats with peripheral inflammation (CFA, 48 hrs). In uninjured rats, capsaicin-evoked (1 µg) WDR activity was completely blocked by intraplantar administration of A-425619 (3-100 nmol). Systemic injection of A-425619 (3-30 µmol/kg, i.v.) reduced WDR responses to thermal stimulation in both CFA-inflamed (47°C) and uninjured (52°C) rats. However, the efficacy of A-425619 to attenuate thermal-evoked WDR activity was significantly greater (P < 0.01) in CFA-treated rats. Both intra-dorsal root ganglion (DRG, L5, 20 nmol) and intraplantar (30-300 nmol) injection of A-425619 reduced WDR responses to thermal stimulation. While the effectiveness of A-425619 was similar between CFA-inflamed and uninjured rats following intraplantar injection, the effects of A-425619 after intra-DRG injection were enhanced in the inflamed rats (compared to the uninjured rats). Spontaneous WDR discharges were unaltered by systemic or site-specific injections of A-425619. Thus, noxious thermal stimulation triggers the transmission of TRPV1-related signals to spinal WDR neurons in both inflamed and uninjured animals. The apparent increase in TRPV1 signalling to WDR neurons following injury may be the result of changes to the distribution/sensitization of peripheral TRPV1 receptors.
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